Transdermal patches have been described extensively in the art to deliver drugs and agents other than vitamin B12 through intact skin. For example, such devices include, but are not limited to, those described in U.S. Pat. Nos. 3,170,795; 3,598,122, 3,598,123; 3,731,683; 3,742,951; 3,814,097; 3,921,636; 3,972,995; 3,993,072; 3,993,073; 3,996,934; 4,031,894; 4,060,084; 4,069,307; 4,077,407; 4,201,211; 4,230,105; 4,286,592; 4,292,299; 4,292,303; 4,314,557; 4,379,454; and 4,568,343, each of which is hereby incorporated by reference in its entirety.
Transdermal delivery offers several advantages as compared to oral delivery and injection, including, but not limited to: 1) avoidance of hepatic first pass metabolism; 2) discontinuing administration easily accomplished by patch removal; 3) improved patient compliance; and 4) maintenance of constant active agent level in blood for longer periods of time. As specifically compared to oral delivery, transdermal delivery decreases the necessary dose to be administered.
The major obstacle to transdermal delivery is the excellent barrier characteristics exhibited by skin. Several routes through the skin have been identified. The transappendageal route transports substances through sweat glands and hair follicles with their sebaceous glands. This route is considered of minor importance due to the very limited area (less than 0.1% of total skin surface). However, large compounds can theoretically be delivered by this route. The transepidermal route consists of transport via diffusion through the cellular layer that includes the stratum corneum (consisting of lipids), viable epidermis (90% water held together by tonofibrils), and dermis (loose connective tissue composed of fibrous protein embedded in an amorphous ground substance).
Increased penetration of the skin barrier is achieved by use of physical methods, biological methods, and chemical penetration enhancers. Physical methods include iontophoresis, sonophoresis, thermal energy, and stripping of the stratum corneum. The biological approach utilizes a therapeutically inactive prodrug that is transported through the skin barrier by physiological mechanisms with the prodrug then being metabolized to produce the therapeutically active drug. Chemical penetration enhancers reversibly decrease the barrier allowing drug permeation.
Ideal enhancers are generally non-toxic, pharmacologically inert, nonallergenic, predictable with immediate effect, amendable to full barrier recovery after removal, compatible with a drug and adjuvants, and cosmetically acceptable. Penetration enhancers can be classified broadly as fatty acids, fatty alcohols, terpenes, sulfoxides, anionic surfactants, cationic surfactants, nonionic surfactants, zwitterionic surfactants, polyols, amides, ureas, lactam, and sugars. The actual mechanism of action by a penetration enhancer may be one or more of the following: 1) disruption of the ordered structure of stratum corneum lipids; 2) interaction with intracellular protein; or 3) improved partitioning of the drug, co-enhancer or solvent into the stratum corneum. It has been found that enhancer mixtures can be more efficient by acting together on one or more of these mechanisms to facilitate permeation.
Dimethyl sulfoxide (DMSO) was recognized over 40 years ago for its ability to open the skin. Hundreds of formulations have since been investigated as potential penetration enhancers. Unfortunately, no reliable means for predicting permeability efficacy yet exist although simple guidelines have been proposed.
It has been demonstrated that macromolecules (1-10 kDa) are able to pass through the skin when mixtures of penetration enhancers are applied. In particular, a mixture of sodium dodecyl sulfate and phenyl piperazine increased skin permeability up to 100-fold for macromolecular drugs including heparin, leutinizing hormone releasing hormone and oligonucleotides.
Unfortunately, vitamin B12 administration by the transdermal route was previously believed to be problematic due to the large size of the vitamin B12 molecule. Cyanocobalamin has a standard molecular weight of 1355. This is considered a large molecule that the skin barrier normally blocks. It is generally understood that molecules of molecular weights of 350 or lower are free to penetrate the dermis. Accordingly, the large molecular size was commonly believed to result in low skin permeation rates and, consequently, sub-optimal vitamin B12 dosages imparting no or negligible health benefits to a subject. In addition, cyanocobalamin is sensitive to ultraviolet radiation due to its inherent organometallic character, so it requires stabilization in order to provide a product with practical shelf-life. To be particularly useful as an over the counter product, any transdermal device for vitamin B12 delivery would therefore need to overcome issues related to at least skin permeation efficiency and shelf life stability.